ROLES OF ENDOTHELIN RECEPTORS IN THE REGIONAL AND SYSTEMIC VASCULAR-RESPONSES TO ET-1 IN THE ANESTHETIZED GANGLION-BLOCKED RAT - USE OF SELECTIVE ANTAGONISTS

1 Endothelin-1 (ET-1) produces vasoconstriction, via activation of ET(A) and ET(B) receptors on vascular smooth muscle, and vasodilatation via ET(B) receptors on endothelial cells. Here we have used the ETA receptor-selective antagonist, BQ-123, the ET(B) receptor-selective antagonist, BQ-788 and the ET(A)/ET(B) receptor non-selective antagonist, PD 145065, to study the role of these receptors in mediating the haemodynamic changes induced by an infusion of ET-1 to the anaesthetized ganglion-blocked rat, 2 Infusion of ET-1 (10 pmol kg(-1) min(-1)) increased the mean arterial pressure (MAP) by 57.5 +/- 5.1 mmHg over 70 min. This presser response was reduced by about 50% by coinfusion of BQ-123 (10 nmol kg(-1) min(-1)), but was unaffected by either BQ-788 (10 nmol kg(-1) min(-1)) or PD 145065 (10 nmol kg(-1) min(-1)). 3 After infusion of ET-1 for 70 min the cardiac output had fallen from 102.6 +/- 11.3 to 55.7 +/- 7.6 ml min(-1) and the total peripheral resistance had increased from 3.24 +/- 0.6 to 10.0 +/- 0.8 mmHg ml(-1) min(-1) (per 100g body weight). BQ-123 decreased the magnitudes of these changes whereas BQ-788 potentiated them. PD 145065 was without effect. 4 ET-1 increased the vascular resistances of all the organs studied except the brain and stomach. These changes were attenuated by BQ-123 in the kidneys, skin, adrenal glands and caecum and potentiated by BQ-788 in the kidneys, small intestine, large intestine and mesentery. PD 145065 had little effect on the individual tissues. 5 Thus, BQ-123, a selective ET(A) receptor antagonist, inhibits the presser and vascular constrictor effects of ET-1 more actively than PD 145065. As BQ-788 potentiates some of the vasoconstrictor effects of ET-1 and increases the effects of ET-1 on total peripheral resistance, the predominant role of ET(B) receptors in the rat circulation is to limit the presser effects of ET-1.